More than 40 years ago, the phenomenon of accelerated repopulation was described in experimental tumors undergoing radiotherapy. Today, the concept of preventing tumor cellular repopulation during treatment is a basic tenet in radiotherapy. In fact, it is one of the four all-important Rs widely taught in radiation oncology textbooks. However, the molecular mechanisms involved in tumor repopulation are still very poorly understood. In this project, we propose a paradigm changing hypothesis with regard to the molecular mechanism of tumor repopulation during radiotherapy. Our hypothesis is that dying cells are responsible for mobilizing and stimulating the surviving tumor cells to repopulate the irradiated tumor through paracrine signaling. Our hypothesis is based on our recent discovery of the Phoenix Rising pathway through which caspase 3 activates paracrine signaling cascades from dying cells to stimulate tissue regeneration and the rapid proliferation of surviving tumor cells in irradiated tumors. We plan to carry out the following in-depth investigations of the roles of caspases and other factors in the Phoenix Rising pathway in tumor response to radiotherapy (specific aim 1). In addition, we plan to examine the roles of downstream factors of caspases in the Phoenix Pathway (specific aim 2). Finally we will attempt to determine if inhibition of caspases or their downstream factors is a feasible strategy to enhance cancer radiotherapy (specific aim 3). We believe our project will provide crucial insights into how tumors relapse after radiotherapy. It also has the potential to facilitate the development of new therapeutics for enhancing cancer radiotherapy.